Memapsin 1 is a close homolog of memapsin 2, or beta-secretase (BACE), whose effect on beta-amyloid precursor protein (APP) leads to the production of beta-amyloid (A beta) peptide. BACE has been shown to play a role in the progression of Alzheimer's disease and type 2 diabetes, also known as diabetes melitus.
Briefly, 171 million individuals were estimated to have diabetes in the world, and this is expected to increase to 366 million by 2030. S. Wild et al., Diabetes Care 27: 1047-1053 (2004). It is no surprise, therefore, that diabetes represents a major illness and development of new effective treatments is of great importance.
Furthermore, Alzheimer's disease is a progressive, degenerative disorder that attacks the brain's nerve cells, or neurons, resulting in loss of memory, thinking and language skills, and behavioral changes. Alzheimer's disease accounts for the majority of senile dementias and is a leading cause of death in adults. Anderson, R. N., Natl. Vital Stat. Rep. 49:1-87 (2001). Histologically, the brain of persons afflicted with Alzheimer's disease is characterized by a distortion of the intracellular neurofibrils and the presence of senile plaques composed of granular or filamentous argentophilic masses with an amyloid protein core, largely due to the accumulation of β-amyloid peptide (Aβ) in the brain. Aβ accumulation plays a role in the pathogenesis and progression of the disease and is a proteolytic fragment of amyloid precursor protein (APP). Selkoe, D. J., Nature 399: 23-31 (1999). APP is cleaved initially by β-secretase followed by γ-secretase to generate Aβ. Lin, X., et al., Proc. Natl. Acad. Sci. USA 97:1456-1460 (2000); and De Stropper, B., et al., Nature 391:387-390 (1998).
Because of the large impact of diabetes and Alzheimer's on the world's population and the apparent paucity of therapeutic agents that treat both diseases by targeting (e.g., inhibiting) memapsin 1, there is a need for compounds designed for inhibiting memapsin 1.